Abstract. The aim of the present study was to investigate dexamethasone (DEX)-induced secretion of cystatin C (Cys C) and the effect of cisplatin (CDDP) and 5-fluorouracil (5-FU) on Cys C secretion in human cancer cell lines. KYSE150, A549 and Caki-2 human cancer cell lines were cultured on plastic dishes and treated with DEX (100 nM) for 24, 48 and 72 h. KYSE150 cells were co-treated with DEX, CDDP (10 µM), and 5-FU (2 µM). The effects of DEX, CDDP and 5-FU on cell viability were evaluated. Results showed Cys C secretion levels in the culture medium of DEX-treated KYSE150 cells to be 1.8-to 2.3-fold higher compared to those in the culture medium of control cells. A similar tendency was observed in A549 cells at all the time points, whereas a significant increase in the Cys C secretion by Caki-2 cells was observed only 24 h after DEX treatment. Regarding KYSE150 cells, the secretion of Cys C was also enhanced by co-treatment of CDDP or 5-FU with DEX, although it was not affected by the co-administration of DEX and mifepristone, a glucocorticoid receptor antagonist. At concentrations that are typically used in esophageal cancer chemotherapy, CDDP and 5-FU demonstrated a moderate level of cytotoxicity in KYSE150 cells in contrast to DEX. These findings suggested that DEX has the potential to enhance the extracellular secretion of Cys C in esophageal cancer cells, possibly due to the transcriptional regulation mediated by glucocorticoid receptor activity. IntroductionCystatin C (Cys C) is a non-glycosylated cationic 13.3-kDa protein belonging to the cystatin superfamily of cysteine protease inhibitors (1-3). Cys C is produced by nucleated cells and is secreted into the blood at a constant rate (1-3). It is freely filtered through the glomerular membrane, completely re-absorbed and then catabolized in the proximal tubular cells (1-3). Thus, similarly to creatinine, the biological fate of Cys C is a good endogenous marker of the glomerular filtration rate (GFR).In patients with esophageal cancer, cisplatin (CDDP) is used as a neoadjuvant or as a post-operative adjuvant chemotherapy in combination with continuous infusion of 5-fluorouracil (5-FU) (4,5). When CDDP-based chemotherapy is administered, antiemetic drugs, such as dexamethasone (DEX), 5-HT 3 serotonin receptor antagonists or aprepitant are administered to prevent treatment-associated nausea and vomiting (6). A transient elevation was previously reported in serum Cys C concentration during the perioperative chemotherapy period in patients with esophageal cancer. We suggested that renal function estimates determined on the basis of serum Cys C levels during this treatment period might be misleading (7).To understand the effect of DEX and other drugs in detail, it is crucial to investigate the renal effects associated with serum Cys C concentration. The aim of this study was to investigate the ability of DEX to induce Cys C secretion in human cancer cell lines, as well as the effect of CDDP, 5-FU and mifepristone (RU-486) on Cys C secretion. Materials and metho...

Significance and Impact of the Study: Drug resistance is common in immunocompromised patients with fungal infections. Curcumin, isolated from Curcuma longa, inhibits drug efflux in nonpathogenic budding yeast Saccharomyces cerevisiae cells overexpressing ABC transporters S. cerevisiae Pdr5p and pathogenic Candida albicans Cdr1p and Cdr2p. We examined the effects of curcumin on multidrug resistance in a wild-type strain of the budding yeast with an intrinsic expression system of multidrug efflux-related genes. Curcumin directly inhibited drug efflux and also suppressed the PDR5 expression, thereby enhancing the antifungal effects. Thus, curcumin potentially promotes the efficacy of antifungals via its effects on ABC transporters in wild-type fungal strains. AbstractDrug resistance commonly occurs when treating immunocompromised patients who have fungal infections. Curcumin, is a compound isolated from Curcuma longa, has been reported to inhibit drug efflux in several human cell lines and nonpathogenic budding yeast Saccharomyces cerevisiae cells that overexpresses the ATP-binding cassette (ABC) transporters S. cerevisiae Pdr5p and pathogenic Candida albicans Cdr1p and Cdr2p. The aim of this study was to examine the effects of curcumin on multidrug resistance in a wild-type strain of the budding yeast with an intrinsic expression system of multidrug efflux-related genes. The antifungal activity of dodecanol alone was temporary against S. cerevisiae; however, restoration of cell viability was completely inhibited when the cells were co-treated with dodecanol and curcumin. Furthermore, restriction of rhodamine 6G (R6G) efflux from the cells and intracellular accumulation of R6G were observed with curcumin treatment. Reverse transcription-polymerase chain reaction analysis revealed that curcumin reduced the dodecanol-induced overexpression of the ABC transporter-related genes PDR1, PDR3 and PDR5 to their control levels in untreated cells. Curcumin can directly restrict the glucose-induced drug efflux and inhibits the expression of the ABC transporter gene PDR5, and can thereby inhibit the efflux of dodecanol from S. cerevisiae cells. Curcumin is effective in potentiating the efficacy of antifungal drugs via its effects on ABC transporters.

Drug resistance in fungal infections has been a more frequent occurrence with the increasing number of immunocompromised patients. In efforts to overcome the problem of fungal drug resistance, we focused on the phenolic compound dehydrozingerone, which is isolated from Zingiber officinale. The effectiveness of this compound on the model yeast Saccharomyces cerevisiae has not been reported. In our study, dehydrozingerone showed a weak antifungal activity against the yeast, but demonstrated a synergistic effect in combination with dodecanol, which typically only restricts cell growth transiently. Efflux of rhodamine 6G through the multidrug efflux pumps was significantly restricted by dehydrozingerone. The transcription level of PDR5, encoding a primary multidrug efflux pump in S. cerevisiae, was enhanced with dodecanol treatment, whereas the level was reduced by dehydrozingerone. These results suggest that dehydrozingerone may be effective for potentiating antifungal activity of other drugs that are expelled from fungi by multidrug transporters like Pdr5p.